The Gentics of Autism

Despite several decades of intense genetic research, we still do not know the primary genetic causes for autism. However, we are sure that autism has a strong genetic basis even though we have identified only a few genes that contribute to this genetic basis. The figure below lists some basic aspects about autism including its high population prevalence, now estimated at 1/150 children. This prevalence number includes the spectrum of different types of autism, as listed.

Children with autism are often evaluated by pediatricians or neurologists in an attempt to find a genetic or medical causation for the problem but about 90% of children with autism have no identifiable causation. In fact, these children are physically well-developed and do not have any known medical or metabolic problems. As many as 10% of autistic children however may have identifiable genetic conditions, and in about 1/2 of them the problem can be detected by routine genetic testing or can be diagnosed by the physical examination that enables the clinician to diagnose a recognizable dysmorphic syndrome. The other 1/2 (5%) require specialized molecular-chromosome studies in order to detect an abnormality, and I have termed this group the "genomic type"as noted in the pie diagram.

The syndromic type of autism is often identified by a routine blood chromosome study that detects gross anomalies such as an extra whole chromosome or a structurally rearranged chromosome. A much smaller percentage of autistic individuals with the syndromic type of autism may have the Fragile X syndrome, detectable by DNA testing. More specialized studies such as flourescence in-situ hybridization (FISH) can detect micro-duplications and deletions that comprise part of the genomic type of autism. For example, microduplication of chromosome region 15q11.2 can cause autistic features and may be present in 1% of those with autism. Extremely high resolution chromosome studies are now being performed on children with autism using the method of array-based comparative genomic hybridization (CGH). CGH can detect extremely small chromosome duplications and deletions that now comprise the genomic type causes for autism.

The majority of children with autism however will have normal genetic and metabolic studies. Yet, we know that there is a genetic basis for autism because, for example, identical twins have a high concordance for autism, sometimes as high as 90%. This indicates a genetic component that is relatively strong since non-identical twins typically do not have concordance rates that exceed 10%. The figure below illustrates data from twin studies.

Other features about autism tell us that there is a genetic basis for it, such as a relatively high recurrence risk of 3-6% in first degree relatives of an individual with autism. Also, the excess male prevalence suggests an influence from the genetic makeup but we do not have evidence for a major gene on the X-chromosome contributing to autism. Additionally, close relatives have an increased risk for certain comorbid conditions (e.g., Obsessive-Compulsive Disorder), and from these observations, we presume that some heritable influence may be operative.

The prevailing theory for autism is that it is a polygenic or multi-factorial genetic disorder. This model, which is a hypothetical one, presumes that there are multiple genes and multiple environmental forces that interact in some complex way to ultimately create the problem of autism. A simplistic way of thinking about this is that these genetic and environmental risk factors push he child over a "threshold" and then autism become manifest.

At present, it is not known what these genes or environmental influences are. Environmental influences could begin very early, during the period of egg or fetal development, and could extend into the postnatal period as indicated below.

The environmental influences could also be factors related to socialization and behavioral issues. The diagram below illustrates that nurturing elements such as the family environment and educational background may in some way prove critical to either the onset of autism or the prevention of this condition. Attempts to manipulate environmental factors, particularly oriented around nutritional issues, are made in the hope that these manipulations may in some way change the neuronal abnormalities associated with autism. Of course, these neuronal abnormalities may have strong genetic underpinnings.